PROJECT SUMMARY - PROJECT 1 The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project (P3) is to discover biological transformations in brain that occur during the perimenopausal transition that lead to endophenotypes predictive of risk for Alzheimer's disease (AD). Our goals are to identify the mechanisms by which these transformations occur and to translate these discoveries into strategies to prevent conversion to an at-AD-risk phenotype. The mission of Project 1 is to provide a mechanistic rationale for the adverse impact of the APOE4 gene in females. Utilizing rodent models of human perimenopause carrying humanized ApoE4, this mission will be accomplished through systems biology analyses of bioenergetic, redox, and inflammatory pathways activated during the perimenopausal transition and their impact for developing an at-AD-risk phenotype through three specific aims: (1) determining the ApoE4- perimenopausal bioenergetic phenotypes most at risk for developing biomarkers of AD; (2) delineating the mechanistic pathways involved in the metabolic-inflammatory axis relevant to development of an at-AD-risk phenotype; and (3) assessing the impact of ovarian hormones on the expression of bioenergetic and inflammatory biomarkers of AD. To address our hypotheses, we will determine bioenergetic gene expression across the perimenopausal transition in the humanized ApoE4 rodents and monitor indicators of mitochondrial function: bioinformatics network analyses of gene expression, in vivo cerebral glucose metabolism, and synaptic transmission. Mechanistic analyses will establish the cross-talk between energy metabolism and inflammatory responses in the perimenopause of ApoE4 rats through the coordinated expression of three modules: (1) Metabolism; (2) Redox Control; and (3) Neuroinflammation. Project 1 collaborates with Projects 2 and 3 to test the hypothesis that decline in brain bioenergetics leads to activation of the inflammatory response in brain that exacerbates mitochondrial function and leads to development of AD pathology (Project 2) and to a bioenergetic phenotype (assessed by neuroimaging) and cognitive decline in perimenopausal and post-menopausal women (Project 3). Outcomes of Project 1 include: (1) basic science discovery of the bioenergetics of the perimenopausal aging transition in ApoE4 carriers vulnerable to development of AD; (2) mechanistic pathways that connect bioenergetics decline to neuroinflammation by redox-controlled pathways in the perimenopausal brain; (3) translational discovery of the window of opportunity for ovarian hormone intervention to prevent impairment of the bioenergetics- inflammatory axis in the ApoE4-positive perimenopausal brain; and (4) clinical associations of glucose metabolism, inflammatory markers and cognitive decline in postmenopausal women.